Nature and history : towards a hermeneutic philosophy of historiography of science

This thesis investigates the role of the natural world - the things studied by natural scientists - in historical accounts of science. It does so through the concepts of contingency and inevitability: it discusses the possibility that the world renders the final development of science inevitable, as well as several theoretical alternatives offered to this possibility. Notable among these alternatives are the Strong Programme in the Sociology of Scientific Knowledge (SSK), Bruno Latour's Actor Network Theory (ANT), and the naturalistic, evolutionary invisible hand model proposed by David Hull. This discussion culminates in a proposal for a hermeneutic perspective on history of science and on the role of the world in it.This work is part of the research programme “Philosophical Foundations of the Historiography of Science” (project 360-20-220) which is financed by the Netherlands Organisation for Scientific Research.UBL - phd migration 201

Children are not like other loads: a cross-cultural perspective on the influence of burdens and companionship on human walking

A major portion of humans’ activity-based energy expenditure is taken up by locomotion, particularly walking. Walking behaviors have energetic outcomes and as such can be important windows into how populations and groups adjust to different environmental and task constraints. While sex differences in the speed of paired walkers have been established by others, the dynamics of how walkers adjust their speed in more varied groups and in groups containing children remains unexplored. Furthermore, little ecological data exists to illustrate the relationships between walking speed and child-carrying. Here, we aim to determine how culture impacts the effects of group composition and infant-carrying on walking speed. Because the determinants of group dynamics and parental investment are partially cultural, we examine walking behavior in the Northwestern United States and in Central Uganda. Using an observational method, we recorded the speed, load carriage, and group composition of pedestrians in a single naturalistic urban environment within each country. Our data suggest that children are treated fundamentally differently than other loads or the presence of walking partners, and that major speed adjustments are child-dependent. Our data furthermore indicate that Ugandans walk more slowly in groups than when alone, while Americans walk more quickly in groups. Clear distinctions between the groups make large generalizations about walking behavior difficult, and highlight the importance of culturally specific contexts

Caprine PRNP polymorphisms N146S and Q222K are associated with proteolytic cleavage of PrPC

Abstract Expression of the cellular prion protein (PrPC) is crucial for the development of prion diseases. Amino acid changes in PrPC or a reduced amount of PrPC may modulate disease resistance. The relative abundance of C1, a natural α-cleavage fragment of PrPC, was previously found to be associated with a resistant PRNP genotype in sheep. Goats are another small ruminant where classical scrapie susceptibility is under strong genetic control. In this study, we assessed PrPC in goats for the existence of similar associations between PrPC fragments and genotype. Brain tissue homogenates from scrapie-free goats with wild type PRNP or polymorphisms (I142M, H143R, N146S, or Q222K) were deglycosylated prior to immunoblot for assessment of the relative abundance of the C1 fragment of PrPC. The presence of K222 or S146 alleles demonstrated significantly different relative levels of C1 compared to that observed in wild type goats, which suggests that the genotype association with C1 is neither unique to sheep nor exclusive to the ovine Q171R dimorphism

Leukocyte Pyruvate Kinase Expression is Reduced in Normal Human Pregnancy but not in Pre-eclampsia

Citation Xu Y, Madsen-Bouterse SA, Romero R, Hassan S, Mittal P, Elfline M, Zhu A, Petty HR. Leukocyte pyruvate kinase expression is reduced in normal human pregnancy but not in pre-eclampsia. Am J Reprod Immunol 2010; 64: 137–151Emerging evidence suggests that metabolism influences immune cell signaling and immunoregulation. To examine the immunoregulatory role of glycolysis in pregnancy, we evaluated the properties of pyruvate kinase in leukocytes from non-pregnant women and those with normal pregnancy and pre-eclampsia.We evaluated pyruvate kinase expression in lymphocytes and neutrophils from non-pregnant, pregnant, and pre-eclampsia patients using fluorescence microscopy and flow cytometry. Leukocyte pyruvate kinase activity and pyruvate concentrations were also evaluated. To study pyruvate’s effect on signaling, we labeled Jurkat T cells with Ca 2+ dyes and measured cell responses in the presence of agents influencing intracellular pyruvate.The expression of pyruvate kinase is reduced in lymphocytes and neutrophils from normal pregnant women in comparison with those of non-pregnant women and pre-eclampsia patients. Similarly, the activity of pyruvate kinase and the intracellular pyruvate concentration are reduced in leukocytes of normal pregnant women in comparison with non-pregnant women and women with pre-eclampsia. Using Jurkat cells as a model of leukocyte signaling, we have shown that perturbations of intracellular pyruvate influence Ca 2+ signals.Normal pregnancy is characterized by reduced pyruvate kinase expression within lymphocytes and neutrophils. We speculate that reduced pyruvate kinase expression modifies immune cell responses due to reduced pyruvate concentrations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79222/1/j.1600-0897.2010.00881.x.pd

Theileria parasites subvert E2F signaling to stimulate leukocyte proliferation

Intracellular pathogens have evolved intricate mechanisms to subvert host cell signaling pathways and ensure their own propagation. A lineage of the protozoan parasite genus Theileria infects bovine leukocytes and induces their uncontrolled proliferation causing a leukemia-like disease. Given the importance of E2F transcription factors in mammalian cell cycle regulation, we investigated the role of E2F signaling in Theileria-induced host cell proliferation. Using comparative genomics and surface plasmon resonance, we identified parasite-derived peptides that have the sequence-specific ability to increase E2F signaling by binding E2F negative regulator Retinoblastoma-1 (RB). Using these peptides as a tool to probe host E2F signaling, we show that the disruption of RB complexes ex vivo leads to activation of E2F-driven transcription and increased leukocyte proliferation in an infection-dependent manner. This result is consistent with existing models and, together, they support a critical role of E2F signaling for Theileria-induced host cell proliferation, and its potential direct manipulation by one or more parasite proteins

Effects of N-Acetylcysteine on Nicotinamide Dinucleotide Phosphate Oxidase Activation and Antioxidant Status in Heart, Lung, Liver and Kidney in Streptozotocin-Induced Diabetic Rats

Purpose: Hyperglycemia increases reactive oxygen species (ROS) and the resulting oxidative stress plays a key role in the pathogenesis of diabetic complications. Nicotinamide dinucleotide phosphate (NADPH) oxidase is one of the major sources of ROS production in diabetes. We, therefore, examined the possibility that NADPH oxidase activation is increased in various tissues, and that the antioxidant N-acetylcysteine (NAC) may have tissue specifc effects on NADPH oxidase and tissue antioxidant status in diabetes. Materials and Methods: Control (C) and streptozotocin-induced diabetic (D) rats were treated either with NAC (1.5 g/kg/ day) orally or placebo for 4 weeks. The plasma, heart, lung, liver, kidney were harvested immediately and stored for biochemical or immunoblot analysis. Results: levels of free 15-F 2t-isoprostane were increased in plasma, heart, lung, liver and kidney tissues in diabetic rats, accompanied with significantly increased membrane translocation of the NADPH oxidase subunit p67phox in all tissues and increased expression of the membrane-bound subunit p22phox in heart, lung and kidney. The tissue antioxidant activity in lung, liver and kidney was decreased in diabetic rats, while it was increased in heart tissue. NAC reduced the expression of p22phox and p67phox, suppressed p67phox membrane translocation, and reduced free 15-F 2t-isoprostane levels in all tissues. NAC increased antioxidant activity in liver and lung, but did not signifcantly affect antioxidant activity in heart and kidney. Conclusion: The current study shows that NAC inhibits NADPH oxidase activation in diabetes and attenuates tissue oxidative damage in all organs, even though its effects on antioxidant activity are tissue specifc. © Yonsei University College of Medicine 2012.link_to_OA_fulltex

Identification of a human neonatal immune-metabolic network associated with bacterial infection

Understanding how human neonates respond to infection remains incomplete. Here, a system-level investigation of neonatal systemic responses to infection shows a surprisingly strong but unbalanced homeostatic immune response; developing an elevated set-point of myeloid regulatory signalling and sugar-lipid metabolism with concomitant inhibition of lymphoid responses. Innate immune-negative feedback opposes innate immune activation while suppression of T-cell co-stimulation is coincident with selective upregulation of CD85 co-inhibitory pathways. By deriving modules of co-expressed RNAs, we identify a limited set of networks associated with bacterial infection that exhibit high levels of inter-patient variability. Whereas, by integrating immune and metabolic pathways, we infer a patient-invariant 52-gene-classifier that predicts bacterial infection with high accuracy using a new independent patient population. This is further shown to have predictive value in identifying infection in suspected cases with blood culture-negative tests. Our results lay the foundation for future translation of host pathways in advancing diagnostic, prognostic and therapeutic strategies for neonatal sepsis